Metal ions are critical to the proper functioning of living systems. Ions such as Fe2+, Zn2+, Cu2+, Ca2+, and Co3+, to name but a few, can be found in the active sites of over a third of known enzymes and other functional proteins such as RNA polymerase, DNA transcription factors, cytochromes P450s, hemoglobin, myoglobin, and coenzymes such as vitamin B12. There, these metals serve to regulate oxidation and reduction reactions, stabilize or shield charge distributions, and orient substrates for reactions.
However, the body has a limited ability to absorb and excrete metals, and an excess can lead to toxicity. As one example, an excess of iron, whether derived from red blood cells chronically transfused, necessary in such conditions such as beta thalassemia major, or from increased absorption of dietary iron such as hereditary hemochromatosis can be toxic through the generation by iron of reactive oxygen species from H2O2. In the presence of Fe2+, H2O2 is reduced to the hydroxyl radical (HO.), a highly reactive species, a process known as the Fenton reaction. The hydroxyl radical reacts very quickly with a variety of cellular constituents and can initiate free radicals and radical-mediated chain processes that damage DNA and membranes, as well as produce carcinogens. Without effective treatment, iron levels progressively increases with deposition in the liver, heart, pancreas, and other endocrine organs. Iron accumulation can result in produce (i) liver disease that may progress to cirrhosis and hepatocellular carcinoma, (ii) diabetes related both to iron-induced decreases in pancreatic β-cell secretion and increases in hepatic insulin resistance and (iii) heart disease, the leading cause of death in β-thalassemia major and other anemia associated with transfusional iron overload. Iron overload is also known to facilitated microbial infection in vertebrates by different strains of fungi, protozoa, gram positive, gram negative and acid-fast bacteria. This condition also facilitates viral infections in humans. Iron overload in humans is known to change the chemotactic and phagocytic properties of neutrophils, which leads to the reduction of their ability to kill invading pathogens. The T-cell function is also affected by these high concentrations of iron.
Other metals, especially those ions with little or no endogenous function, may find their way into the body and effect damage. Heavy metal ions such as Hg2+ can replace ions such as Zn2+ in metalloproteins and render them inactive, resulting in serious acute or chronic toxicity that can end in death or cause birth defects. Even more significantly, radioactive isotopes of the lanthanide and actinide series can cause grave illness to an individual exposed to them by mouth, air, or skin contact. Such exposure could result not only from the detonation of a nuclear bomb or a “dirty bomb” composed of nuclear waste, but also from the destruction of a nuclear power facility.
Traditional standard therapies for metal overload include the use of metal chelators such as deferoxamine (DFO, N′-[5-(acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl)propanoylamino]pentyl]-N-hydroxy-butane diamide). DFO is an effective metal chelator; unfortunately, it is not orally bioavailable and has a very short half-life in serum. More recently, other metal chelators have been developed for clinical use, but have serious side effects including life-threatening agranulocytosis (deferiprone, Ferriprox™), renal and liver toxicity (deferesirox, Exjade™). Others are not as effective and require repeated daily doses.
Therefore, there is still a great need for a safe, effective and orally active metal chelator for the treatment of metal overload.